Preparation of terpyridines

ABSTRACT

Process for preparing terpyridines of the formula I  
                 
 
     in which  
     R are hydrogens or identical C 1 -C 12 -alkyl or C 1 -C 12 -alkoxy radicals and  
     n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals R,  
     comprises the successive reaction steps:  
     A′) acid hydrolysis of a 2-cyanopyridine derivative by means of an anhydrous inorganic acid or its anhydride in the presence of water and a C 1 -C 4 -alkanol, with an equimolar amount of water being added to the 2-cyanopyridine derivative prior to addition of the anhydrous inorganic acid or its anhydride,  
     A) condensation of the C 1 -C 4 -alkyl pyridine-2-carboxylate derivative obtained in reaction step A′ with acetone in an aprotic solvent in the presence of an alkali metal C 1 -C 4 -alkoxide or alkaline earth metal C 1 -C 4 -alkoxide as base,  
     B) reaction of the 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivative obtained in reaction step A with ammonia or ammonium salts (NH 4 ) q Y with removal of the water of reaction formed using a C 1 -C 4 -alkanol as entrainer, where the variable Y in (NH 4 ) q Y is the 40 anion of the parent q-basic acid H q Y of the ammonium salt, and  
     C) chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative obtained in reaction step B using phosphorus oxide chloride (POCl 3 ) or using a mixture comprising phosphorus oxide chloride and at least one organic solvent selected from the group consisting of toluene, o-xylene, m-xylene and p-xylene.  
     Also provided are a process for preparing C 1 -C 4 -alkyl pyridine-2-carboxylate derivatives from 2-cyanopyridine derivatives, a process for preparing 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivatives by condensation of a C 1 -C 4 -alkyl pyridine-2-carboxylate derivative with acetone, a process for preparing 2,6-bis(2-pyridyl)-4(1H)pyridinone derivatives by reaction of a 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivative with ammonia or ammonium salts and a process for preparing terpyridines of the formula I by chlorination of a 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative.

[0001] The present invention relates to a process for preparingterpyridines of the formula I

[0002] in which

[0003] R are hydrogens or identical C₁-C₁₂-alkyl or C₁-C₁₂-alkoxyradicals and

[0004] n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals

[0005] by successive reaction steps comprising

[0006] A) condensation of a C₁-C₄-alkyl pyridine-2-carboxylatederivative with acetone in an aprotic solvent in the presence of a base,

[0007] B) reaction of the 1,5-bis(2-pyridyl)pentane-1,3,5-trionederivative obtained in reaction step A with ammonia or ammonium salts(NH₄)_(q)Y with removal of the water of reaction formed, where thevariable Y in (NH₄)_(q)Y is the anion of the parent q-basic acid H_(q)Yof the ammonium salt, and

[0008] C) chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinonederivative obtained in reaction step B,

[0009] wherein the reaction step A is preceded by a reaction step A′ inwhich the C₁-C₄-alkyl pyridine-2-carboxylate derivative is obtained by

[0010] A′) acid hydrolysis of a 2-cyanopyridine derivative by means ofan anhydrous inorganic acid or its anhydride in the presence of waterand a C₁-C₄-alkanol, with an equimolar amount of water being added tothe 2-cyanopyridine derivative of the formula a prior to addition of theanhydrous inorganic acid or its anhydride,

[0011] the base used in reaction step A is an alkali metalC₁-C₄-alkoxide or alkaline earth metal C₁-C₄-alkoxide,

[0012] the removal of the water of reaction in reaction step B iscarried out using a C₁-C₄-alkanol as entrainer

[0013] and

[0014] the chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinonederivative of the formula c in reaction step C is carried out usingphosphorus oxide chloride (POCl₃) or using a mixture comprisingphosphorus oxide chloride and at least one organic solvent selected fromthe group consisting of toluene, o-xylene, m-xylene and p-xylene.

[0015] The present invention further relates to a process for preparingC₁-C₄-alkyl pyridine-2-carboxylate derivatives from 2-cyanopyridinederivatives, to a process for preparing1,5-bis(2-pyridyl)pentane-1,3,5-trione derivatives by condensation of aC₁-C₄-alkyl pyridine-2-carboxylate derivative with acetone, to a processfor preparing 2,6-bis(2-pyridyl)-4(1H)pyridinone derivatives by reactionof a 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivative with ammonia orammonium salts and to a process for preparing terpyridines of theformula I by chlorination of a 2,6-bis(2-pyridyl)-4(1H)pyridinonederivative.

[0016] The interest in oligopyridines is tremendous, particularlybecause they are excellent complexing agents for metals. As a result, awide variety of synthetic routes have been employed for these compounds.A review is given, for example, by R. -A. Fallahpour in Synthesis 2000,No. 12, 1665-1667.

[0017] The synthesis of 4′-chloro-2,2′:6′,6″-terpyridine from ethylpyridine-2-carboxylate via the intermediates1,5-bis(2-pyridyl)pentane-1,3,5-trione and2,6-bis(2-pyridyl)-4(1H)pyridinone is described by E. C. Constable andM. D. Ward in J. Chem. Soc. Dalton Trans. 1990, 1404-1409 (1). Thecondensation of the pyridinecarboxylic ester with acetone (correspondingto reaction step A of the process of the present invention) is carriedout in the presence of sodium 45 hydride as base. The resultingpentane-1,3,5-trione is then reacted with ammonium acetate under refluxto form the corresponding 4(1H)pyridinone (corresponding to reactionstep B of the process of the present invention), which then reacts withan excess of phosphorus pentachloride in phosphorus oxide chloride assolvent to give the desired terpyridine (corresponding to reaction stepC of the process of the present invention). The respective yields of thereactions corresponding to the reaction steps A, B and C are said by theauthors to be 80%, 80% and 62%, respectively, which corresponds to anoverall yield of terpyridine based on the pyridinecarboxylic ester usedof about 40%.

[0018] According to R. L. Frank and E. F. Riener, J. Am. Chem. Soc.,Vol. 72, 4182-4183 (2), ethyl picolinate (ethyl pyridine-2-carboxylate)is prepared by reacting 2-cyanopyridine with ethanol saturated with HClgas. The imino ester formed as intermediate is then hydrolyzed to theethyl ester by pouring into water. The yield of this reaction is said tobe 40%.

[0019] Serious disadvantages of the procedure described in (1) are theuse of extremely air- and moisture-sensitive sodium hydride and of largeamounts of corrosive and toxic phosphorus pentachloride or phosphorusoxide chloride and the generally high starting material costs forpyridinecarboxylic esters. For these reasons, this route to terpyridinescan be employed only with great difficulty, if at all, on a (large)industrial scale.

[0020] An attractive starting material for the synthesis of terpyridinesis 2-cyanopyridine, because of the price advantage overpyridinecarboxylic esters. 2-Cyanopyridine can be converted as describedin (2) into ethyl pyridinecarboxylates, but the synthesis described in(2) has the disadvantage that, based on the amount of 2-cyanopyridineused, only a small yield of the desired ester is obtained, which cancelsout the price advantage. If the yield reported in (2) is multiplied bythe yield of about 40% indicated above, the overall yield of terpyridinestarting from 2-cyanopyridine is only about 16%. This is prohibitivelylow for (large-scale) industrial processes.

[0021] It is an object of the present invention to provide aninexpensive process for preparing terpyridines from 2-cyanopyridinewhich can be carried out on a (large) industrial scale and is acceptablefrom the points of view of occupational hygiene and the environment.

[0022] We have found that this object is achieved by a process forpreparing terpyridines of the formula I

[0023] in which

[0024] R are hydrogens or identical C₁-C₁₂-alkyl or C₁-C₁₂-alkoxyradicals and

[0025] n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals R,

[0026] by successive reaction steps comprising

[0027] A) condensation of a C₁-C₄-alkyl pyridine-2-carboxylatederivative of the formula a

[0028]  with acetone in an aprotic solvent in the presence of a base,

[0029] B) reaction of the 1,5-bis(2-pyridyl)pentane-1,3,5-trionederivative of the formula b

[0030]  obtained in reaction step A with ammonia or ammonium salts(NH₄)_(q)Y with removal of the water of reaction formed, where thevariable Y in (NH₄)_(q)Y is the acid anion of the parent q-basic acidH_(q)Y of the ammonium salt, and

[0031] C) chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinonederivative of the formula c obtained in reaction step B

[0032]  where Z is NH in the case of a reaction with ammonia in reactionstep B and is NH₂ ^(⊕) [Y_(1/q)]^(⊖) in the case of a reaction withammonium salts (NH₄)_(q)Y in reaction step B,

[0033] wherein

[0034] the reaction step A is preceded by a reaction step A′ in whichthe C₁-C₄-alkyl pyridine-2-carboxylate derivative of the formula a isobtained by

[0035] A′) acid hydrolysis of a 2-cyanopyridine derivative of theformula a′

[0036]  by means of an anhydrous inorganic acid or its anhydride in thepresence of water and a C₁-C₄-alkanol, with an equimolar amount of waterbeing added to the 2-cyanopyridine derivative of the formula a′ prior toaddition of the anhydrous inorganic acid or its anhydride,

[0037] the base used in reaction step A is an alkali metalC₁-C₄-alkoxide or alkaline earth metal C₁-C₄-alkoxide,

[0038] the removal of the water of reaction in reaction step B iscarried out using a C₁-C₄-alkanol as entrainer and

[0039] the chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinonederivative of the formula c in reaction step C is carried out usingphosphorus oxide chloride (POCl₃) or using a mixture comprisingphosphorus oxide chloride and at least one organic solvent selected fromthe group consisting of toluene, o-xylene, m-xylene and p-xylene.

[0040] In formula a, C₁-C₄-alkyl radicals are methyl, ethyl, n-propyl,i-propyl, n-butyl, i-butyl, sec-butyl and tert-butyl, so that thecorresponding C₁-C₄-alkanols with which the 2-cyanopyridines of theformula a′ are reacted to form the compounds of the formula a aremethanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol,sec-butanol and tert-butanol.

[0041] The latter listing also encompasses the C₁-C₄-alkanols which areused in reaction step B as entrainers for removing the water ofreaction. The alkanols used in steps A′ and B do not necessarily have tobe identical.

[0042] C₁-C₁₂-Alkyl radicals R in the formulae I, a, b, c and a′ can be,in addition to the abovementioned C₁-C₄-alkyl radicals, pentyl,sec-pentyl, tert-pentyl, neopentyl, 2,3-dimethyl-2-butyl, hexyl,2-methylpentyl, heptyl, 2-methylhexyl, 2-ethylhexyl, octyl, isooctyl,2-ethylhexyl, nonyl, 2-methylnonyl, isononyl, 2-methyloctyl, decyl,isodecyl, 2-methylnonyl, undecyl, isoundecyl, dodecyl and isododecyl,(the names isooctyl, isononyl and isodecyl are trivial names and arederived from the carbonyl compounds obtained in the oxo process; cf.Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition, Vol. Al,pages 290-293, and Vol. Alo, pages 284 and 285).

[0043] C₁-C₁₂-Alkoxy radicals R in the formulae I, a, b, c and a′ andthe C₁-C₄-alkoxide radicals of the alkali metal or alkaline earth metalalkoxides to be used as bases in step A are derived from theabovementioned C₁-C₁₂-alkyl or C₁-C₄-alkyl radicals.

[0044] To convert the 2-cyanopyridine derivative of the formula a′ intothe corresponding C₁-C₄-alkyl pyridine-2-carboxylate of the formula a,the former is usually dissolved or suspended in an excess of thecorresponding absolute C₁-C₄-alkanol, admixed with the equivalent amountof water, based on the number of moles of the compound of the formulaa′, and the anhydrous inorganic acid is added, if appropriate a littleat a time. It is naturally also possible to use alkanols with theirtypical residual water contents, in which case the amount of water isthen reduced correspondingly.

[0045] The molar ratio of 2-cyanopyridine derivative to inorganic acidis usually from 1:4 to 1:10, and that of 2-cyanopyridine derivative toC₁-C₄-alkanol is usually from 1:15 to 1:40.

[0046] The reaction conditions in reaction step A′ are usually chosen ina manner analogous to the conditions in the Pinner reaction leading tothe imino esters, i.e. the inorganic acid is added at room temperatureor slightly elevated temperature, which normally results in a furthertemperature increase due to the exothermic character of the reaction.The mixture is then usually allowed to react to completion under reflux.

[0047] The crude product obtained is generally worked up by distillingoff the excess C₁-C₄-alkanol, taking up the residue in a suitablesolvent and, to avoid possible hydrolysis of the ester formed, washinguntil neutral with the solution of a weak base, e.g. an aqueous sodiumbicarbonate solution. After phase separation, the resulting solution ofthe product can, if a suitable aprotic solvent has been used, beprocessed further directly as described in step A or an appropriatesolvent replacement has to be carried out beforehand.

[0048] Examples of anhydrous inorganic acids are anhydrous sulfuricacid, fuming sulfuric acid, anhydrous phosphoric acid, anhydrouspyrophosphoric acid and hydrogen chloride, with preference being givento using the latter.

[0049] Examples of anhydrides of these inorganic acids are sulfurtrioxide and tetraphosphorus decaoxide.

[0050] As alkali metals or alkaline earth metals of the alkoxides instep A, particular mention may be made of sodium and potassium and alsomagnesium and calcium, especially sodium. Preference is accordinglygiven to using sodium C₁-C₄-alkoxides, in particular sodium methoxide.

[0051] Aprotic solvents which can be used in step A are generally wellknown to those skilled in the art. Examples are cyclic ethers such astetrahydrofuran or dioxane, and also linear and branched glycol etherswhich are obtainable from ethylene oxide and propylene oxide. Examplesof such ethers are dimethoxyethane (DME) and further dimethyl etherswhich are commercially available under the name Glyme®.

[0052] The reaction conditions in step A correspond to the usualconditions of the Claisen condensation, i.e. the reaction is normallycarried out under reflux at the boiling point of the solvent used.

[0053] The molar ratio of ester derivative of the formula a to acetoneis usually 2:1, corresponding to the stoichiometry of the reaction. Inspecific cases, slightly above or slightly below this ratio may bedesirable.

[0054] The crude product obtained in step A is generally sufficientlypure and can therefore normally be used as starting material forreaction step B without elaborate purification. Thus, after adjustingthe pH to a neutral or slightly acid value by means of a weak acid, e.g.acetic acid or the ammonium salt (NH₄)_(q)Y to be used in step B, theentrainer for step B can be added directly to the solution/suspensionobtained in step A.

[0055] However, if higher purities are required, it is possible toseparate off the aprotic solvent used in step A, dissolve or suspend theresidue in water, add a weak acid, e.g. acetic acid, until the pH isneutral or slightly acid, filter off the usually solid reaction productwith suction and wash it with a little water. If necessary, this can befollowed by a drying step.

[0056] As solvent or suspension medium in reaction step B, use is madeof the C₁-C₄-alkanol serving as entrainer. The molar ratio of trionederivative of the formula b to alkanol is usually from 1:75 to 1:125.

[0057] The removal of the water of reaction in reaction step B iscarried out using customary methods of water separation. If the alkanolserving as entrainer has only limited miscibility with water, forinstance in the case of the various C₄-alkanols, the water can beremoved, for example, by discharging it after phase separation and thealkanol can be returned to the reaction mixture. If the alkanol andwater have unlimited miscibility, the water can be separated off bydistillation together with the alkanol and the latter can be worked upin a separate distillation step.

[0058] The reaction temperature in step B corresponds essentially to thecustomary temperatures in the refluxing C₁-C₄-alkanol/water mixture,with lower temperatures or temperature profiles also being able to beset at the beginning of the reaction.

[0059] Preferred entrainers in reaction step B are ethanol, n-propanol,i-propanol and n-butanol, with particular preference being given toethanol.

[0060] Possible ammonium salts (NH₄)_(q)Y with which the trione obtainedin step A is reacted in reaction step B are, for example, the ammoniumsalts of formic, acetic, carbonic, hydrochloric, sulfuric or phosphoricacid, i.e. NH₄HCO₂ (q=1, Y=HCO₂ ^(⊖)), NH₄CH₃CO₂ (q=1, Y=CH₃CO₂ ^(⊖)),NH₄HCO₃ (q=1, Y=HCO₃ _(⊖)), (NH₄)₂CO₃ (q=2, Y=CO₃ ^(2⊖)), NH₄Cl (q=1,Y=Cl^(⊖)), NH₄HSO₄ (q=1, Y=HSO₄ ^(⊖)), (NH₄)₂SO₄ (q=2, Y SO₄ ^(2⊖)),NH₄H₂PO₄ (q=1, Y=H₂PO₄ ^(⊖)) und (NH₄)₂HPO₄ (q=2, Y=HPO₄ ^(2⊖)).Preference is given to using ammonia in step B.

[0061] The ammonium salts are usually used as solids if appropriate withtheir typical contents of water of crystallization, and ammonia isusually used as gas. However, aqueous solutions can also be used ifdesired, in which case not only the water arising in the formation ofthe 4(1H)pyridinone derivative but also the water of the solution areremoved by means of the entrainer in step B.

[0062] The ammonium salts are generally added in a molar ratio ofammonium ion:trione of from 3:1 to 12:1, preferably in a molar ratio offrom 5:1 to 10:1.

[0063] The gaseous ammonia is introduced into the reaction mixture as afinely divided stream, e.g. through a frit, until a molar ratio of thetotal amount of ammonia:trione of from 6:1 to 14:1, preferably from 8:1to 12:1, has been reached. The introduction of the ammonia gas can becarried out initially at temperatures or temperature profiles belowreflux conditions or right from the start under the conditions ofremoval of the water of reaction, i.e. under reflux.

[0064] The crude product obtained in step B is usually worked up bydistilling off the remaining C₁-C₄-alkanol, suspending the residue inwater, filtering it off with suction, washing it with water and a little(!), optionally (ice) cooled, ethanol and finally L drying it.

[0065] The pyridinone obtained in step B is reacted in step C withphosphorus oxide chloride (POCl₃) or with a mixture comprisingphosphorus oxide chloride and at least one organic solvent selected fromthe group consisting of toluene, o-xylene, m-xylene and p-xylene. Thereaction is generally carried out under reflux with boiling of thephosphorus oxide chloride or the mixture of phosphorus oxide chlorideand organic solvent.

[0066] The molar ratio of pyridinone of the formula c to phosphorusoxide chloride is usually from 1:5 to 1:25, in particular from 1:8 to1:20. If a mixture of phosphorus oxide chloride and organic solvent isused, the molar excess of phosphorus oxide chloride over the pyridinonecan be reduced.

[0067] The molar ratio of phosphorus oxide chloride to the organicsolvent is usually from 0.8:1 to 2:1, in particular from 1:1 to 1.5:1.

[0068] The crude product obtained in step C is normally worked up byremoving (e.g. distilling off) the excess phosphorus oxide chloride orthe mixture of phosphorus oxide chloride and organic solvent, dissolvingthe residue (ammonium salt!) in water, bringing the pH to 7 by addingconcentrated alkali (e.g. sodium hydroxide solution, sodium carbonatesolution) or a basic compound (e.g. sodium hydroxide, sodium carbonate),filtering off the resulting precipitate with suction, washing with waterand finally drying the solid.

[0069] The present invention further provides a process for preparingC₁-C₄-alkyl pyridine-2-carboxylate derivatives of the formula a

[0070] in which

[0071] R is hydrogen or a C₁-C₁₂-alkyl or C₁-C₁₂-alkoxy radical and

[0072] n is 0, 1, 2, 3 or 4,

[0073] by acid hydrolysis of a 2-cyanopyridine derivative of the formulaa′

[0074] by means of an anhydrous inorganic acid or its anhydride in thepresence of water and a C₁-C₄-alkanol, wherein an equimolar amount ofwater is added to the 2-cyanopyridine derivative of the formula a′ priorto addition of the anhydrous inorganic acid or its anhydride.

[0075] Reaction conditions for this process have already been describedunder step A′ of the process of the present invention for preparingterpyridines of the formula I from 2-cyanopyridine derivatives of theformula a′ and apply analogously here.

[0076] The present invention also provides a process for preparing1,5-bis(2-pyridyl)pentane-1,3,5-trione derivatives of the formula b

[0077] in which

[0078] R are hydrogens or identical C₁-C₁₂-alkyl or C₁-C12-alkoxyradicals and

[0079] n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals R,

[0080] by condensation of the C₁-C₄-alkyl pyridine-2-carboxylatederivative of the formula a

[0081] with acetone in an aprotic solvent in the presence of an alkalimetal C₁-C₄-alkoxide or alkaline earth metal C₁-C₄-alkoxide as base.

[0082] Bases used are, in particular, alkali metal C₁-C₄-alkoxides,preferably sodium C₁-C₄-alkoxides and particularly preferably sodiummethoxide.

[0083] Further reaction conditions for this process have been describedunder step A of the process of the present invention for preparingterpyridines of the formula I from 2-cyanopyridine derivatives of theformula a′ and apply analogously here.

[0084] Furthermore, the present invention provides a process forpreparing 2,6-bis(2-pyridyl)-4(1H)pyridinone derivatives of the formulac

[0085] in which

[0086] R are hydrogens or identical C₁-C₁₂-alkyl or C₁-C₁₂-alkoxyradicals,

[0087] n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals R,

[0088] Z is NH or NH₂ ^(⊖)[Y_(1/q)]^(⊖) and Y is the anion of a q-basicacid H_(q)Y,

[0089] by reacting the 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivativeof the formula b

[0090] with ammonia or ammonium salts (NH₄)_(q)Y with removal of thewater of reaction formed, wherein the removal of the water of reactionis carried out using a C₁-C₄-alkanol as entrainer.

[0091] As entrainer for removing the water of reaction, use is made, inparticular, of ethanol, n-propanol, i-propanol or n-butanol, withpreference being given to ethanol.

[0092] Further reaction conditions for this process have already beendescribed under step B of the process of the present invention forpreparing terpyridines of the formula I from 2-cyanopyridine derivativesof the formula a′ and apply analogously here.

[0093] Also provided is a process for preparing terpyridines of theformula I

[0094] in which

[0095] R are hydrogens or identical C₁-C₁₂-alkyl or C₁-C₁₂-alkoxyradicals,

[0096] n is 0, 1, 2, 3 or 4 and is the same for both sets of radicals

[0097] Z′ is nitrogen or NH^(⊕)[Y_(1/q)]^(⊖) and

[0098] Y is the acid anion of a q-basic acid H_(q)Y,

[0099] by chlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinonederivative of the formula b

[0100] where Z is NH or NH₂ ^(⊕) [Y_(1/q)]^(⊖),

[0101] wherein the chlorination is carried out using phosphorus oxidechloride (POCl₃) or using a mixture comprising phosphorus oxide chlorideand at least one organic solvent selected from the group consisting oftoluene, o-xylene, m-xylene and p-xylene.

[0102] Chlorinating agents which can be used are, in particular,phosphorus oxide chloride (POCl₃) or a mixture comprising phosphorusoxide chloride and toluene.

[0103] Further reaction conditions-for this process have already beendescribed under step C of the process of the present invention forpreparing terpyridines of the formula I from 2-cyanopyridine derivativesof the formula a′ and apply analogously here.

EXAMPLES

[0104] Reaction Step A′:

[0105] In a 500 ml reaction vessel, 20.8 q (0.2 mol) of 2-cyanopyridinewere dissolved in 300 ml of absolute ethanol. After addition of 3.6 g(0.2 mol) of water, the reaction mixture was heated to 40° C. About 60 gof hydrogen chloride gas were subsequently passed into the mixture overa period of 2 hours, resulting in a rise in the reaction temperature to55° C. After about 45 minutes, a white precipitate formed. Afterintroduction of hydrogen chloride was complete, the reaction mixture washeated to 80° C. and maintained at this temperature for anafter-reaction time of 3 hours. The solvent was subsequently removed ona rotary evaporator, the residue was taken up in 50 ml of water and thepH was adjusted to 7.5 by means of sodium bicarbonate solution. Theaqueous phase was extracted three times with 200 ml each time of ethylacetate and the combined extracts were subsequently dried over sodiumsulfate. After filtration and removal of the solvent on a rotaryevaporator at 60° C./25 hPa, the ethyl pyridine-2-carboxylate remainedas a colorless liquid. The yield was 28.2 g (93.4% of theory).

[0106] Reaction step A:

[0107] A/1: Reaction of ethyl pyridine-2-carboxylate with acetone:

[0108] In a 1 l flask provided with a stirrer, a suspension of 19.5 g(362 mmol) of sodium methoxide in 160 ml of tetrahydrofuran (THF) washeated to reflux (about 66° C.) under a blanket of nitrogen. A solutionof 37.9 g (251 mmol) of ethyl pyridine-2-carboxylate and 8.7 ml (6.9 g,120 mmol) of acetone in 200 ml of THF was subsequently added dropwiseover a period of 4 hours, the reaction mixture was refluxed for afurther 1.5 hours and the THF was taken off under reduced pressure.

[0109] The orange-red solid which remained was dissolved in 450 ml ofwater and neutralized with 5% strength acetic acid, resulting inprecipitation of a yellow solid.

[0110] The crystalline precipitate was filtered off with suction andwashed with a little water and three times with 25 ml each time of coldethanol.

[0111] Drying in a vacuum drying oven at 40° C. gave 23.9 g (74.6% oftheory) of yellowish olive green crude product of the compound

[0112] having a melting point of 92-94° C.

[0113] Recrystallization of a sample of the product from water/ethanol(150 ml: 250 ml) gave olive green crystals having a melting point of99-100° C.

[0114] Recrystallization of 20 g of a sample of the product fromn-hexane/ethanol (150 ml: 250 ml) gave 13 g of olive green crystalshaving a melting point of 101-102° C.

[0115] A/2: Reaction of Ethyl Pyridine-2-carboxylate with Acetone:

[0116] In a 4 l flask provided with a stirrer, a suspension of 195.4 g(3.617 mol) of sodium methoxide in 1000 ml of tetrahydrofuran (THF) washeated to reflux (about 66° C.) under a blanket of nitrogen. A solutionof 379.3 g (2.514 mol) of ethyl pyridine-2-carboxylate and 92.3 ml (73.0g, 1.257 mol) of acetone in 1000 ml of THF was subsequently addeddropwise over a period of 4 hours, the reaction mixture was refluxed fora further 1.5 hours and the THF was taken off at 60° C./35 hPa.

[0117] The orange-red solid which remained was dissolved in 4000 ml ofwater and neutralized with about 5% strength acetic acid, resulting inprecipitation of a yellow solid and formation of a thick suspension. Themixture was stirred for another hour, and the precipitate was thenfiltered off with suction and washed three times with 120 ml each timeof water.

[0118] Drying in a vacuum drying oven at 50° C. gave 187 g (55.5% oftheory) of olive green crude product of the compound

[0119] having a melting point of 91-92° C.

[0120] Reaction Step B:

[0121] B/1: Reaction of 1,5-bis(2-pyridyl)pentane-1,3,5-trione withAmmonium formate:

[0122] In a 1 l flask provided with a stirrer, water separator andreflux condenser, a solution of 20.4 g (77.0 mmol) of1,5-bis(2-pyridyl)pentane-1,3,5-trione and 34.0 g (539 mmol) of ammoniumformate in 500 ml of absolute ethanol was refluxed at 79° C.

[0123] After the solution had been heated for 30 minutes, a total ofabout 350 ml of ethanol/water were separated off over a period of 6hours. The dark brown reaction solution was allowed to stand overnight,allowed to cool to room temperature and evaporated to about 100 ml on arotary evaporator.

[0124] The concentrate obtained was cooled in ice, the crystallineprecipitate was filtered off with suction and washed twice with a littlecold ethanol and twice with about 20 ml of water.

[0125] Drying in a vacuum drying oven at 50° C. gave 10 g (44.3% oftheory) of light-brown, crystalline crude product of the compound

[0126] having a melting range of 104-114° C.

[0127] Recrystallization of a sample of the crude product fromn-hexane/ethanol (1:2) gave light-beige crystals having a melting rangeof 120° C.-125° C.

[0128] B/2: Reaction of 1,5-bis(2-pyridyl)pentane-1,3,5-trione withAmmonium acetate:

[0129] In a 2 l flask provided with a stirrer, water separator andreflux condenser, a solution of 61.1 g (231 mmol) of1,5-bis(2-pyridyl)pentane-1,3,5-trione and 124.6 g (1.617 mol) ofammonium acetate in 1500 ml of absolute ethanol was refluxed at 78° C.

[0130] After the solution had been heated for 30 minutes, a total ofabout 1200 ml of ethanol/water were separated off over a period of 6hours while the temperature was increased to a final temperature of 83°C. The dark brown reaction solution was allowed to stand over theweekend, allowed to cool to room temperature and evaporated to about 300ml on a rotary evaporator.

[0131] The concentrate obtained was cooled in ice, and the crystallineprecipitate was filtered off with suction and washed twice with a littlecold ethanol.

[0132] Drying in a vacuum drying oven at 50° C. gave 53.5 g (75.46% oftheory) of light-brown, crystalline crude product of the compound

[0133] having a melting point of 128-131° C.

[0134] B/3: Reaction of 1,5-bis(2-pyridyl)pentane-1,3,5-trione withAmmonium carbonate:

[0135] In a 2 l flask provided with a stirrer, water separator andreflux condenser, a solution of 40.8 g (154 mmol) of1,5-bis(2-pyridyl)pentane-1,3,5-trione and 52.0 g (540 mmol) of ammoniumcarbonate in 1000 ml of absolute ethanol was refluxed at 72° C.

[0136] After the solution had been heated for 30 minutes, a total ofabout 700 ml of ethanol/water were separated off over a period of 6hours while the temperature was increased to a final temperature of 79°C. During this procedure, a sublimate, presumably ammonium carbonate,was deposited in the water separator and condenser.

[0137] The dark brown reaction solution was allowed to stand overnight,allowed to cool to room temperature and evaporated on a rotaryevaporator at 60° C./40 hPa. The dark, resinous residue was admixed with200 ml of water, stirred and the crystalline mass formed was filteredoff with suction, washed twice with 50 ml each time of water and oncewith 20 ml of cold ethanol.

[0138] Drying in a vacuum drying oven at 50° C. gave 29 g (75.6% oftheory) of brown, crystalline crude product of the compound

[0139] which displayed two melting ranges at 128-131° C. and 154-157° C.

[0140] Recrystallization of the crude product from a mixture of 300 mlof ethyl acetate and 50 ml of ethanol with cooling to −10° C. by meansof an ice/sodium chloride mixture gave light-brown crystals which werefiltered off with suction and dried at 50° C. in a vacuum drying oven.The yield was 8.8 g and the melting point was 167-169° C.

[0141] The filtrate from the recrystallization was concentrated on arotary evaporator and taken up in 60 ml of ethanol. Cooling to −10° C.by means of an ice/sodium chloride mixture gave light-brown crystalswhich were filtered off with suction and dried at 50° C. in a vacuumdrying oven. The yield from the secondary crystallization was 5.4 g andthe melting point was 170-173° C.

[0142] Precipitation of the filtrate with n-hexane gave another 0.9 g ofbrown crystals which were likewise filtered off with suction and driedat 50° C. in a vacuum drying oven. The melting point of this fractionwas 167-170° C.

[0143] The total yield of these three fractions was 15.1 g (39.4% oftheory).

[0144] B/4: Reaction of 1,5-bis(2-pyridyl)pentane-1,3,5-trione withAmmonium hydrogencarbonate:

[0145] In a 2 l flask provided with a stirrer, water separator andreflux condenser, a solution of 40.8 g (154 mmol) of1,5-bis-(2-pyridyl)pentane-1,3,5-trione and 85.3 g (1.08 mol) ofammonium hydrogencarbonbate in 1000 ml of absolute ethanol was refluxedat 75° C.

[0146] After the solution had been heated for 30 minutes, a total ofabout 600 ml of ethanol/water were separated off over a period of 6hours while the temperature was increased to a final temperature of 79°C. Once again, a sublimate, presumably ammonium (hydrogen)carbonate,deposited in the water separator and condenser.

[0147] The dark brown reaction solution was allowed to stand overnight,allowed to cool to room temperature and evaporated at 60° C./40 hPa on arotary evaporator. The dark, resinous residue was admixed with 200 ml ofwater, stirred and the crystalline mass formed was filtered off withsuction, washed twice with 30 ml each time of water and once with 20 mlof cold ethanol.

[0148] Drying in a vacuum drying oven at 50° C. gave 29.4 g (77.4% oftheory) of brown, crystalline crude product of the compound

[0149] having a melting range of 147-156° C.

[0150] Recrystallization of the crude product from a mixture of 100 mlof n-hexane and 260 ml of ethanol with cooling to −10° C. by means of anice/sodium chloride mixture gave beige/light-brown crystals which werefiltered off with suction and dried at 50° C. in a vacuum drying oven.The yield was 14 g and the melting point was 169-172° C.

[0151] The filtrate from the recrystallization was concentrated to about50 ml on a rotary evaporator and cooling to −10° C. by means of anice/sodium chloride mixture gave light to medium brown crystals whichwere filtered off with suction and dried at 50° C. in a vacuum dryingoven. The yield from the secondary crystallization was 6 g and themelting point was 169-172° C.

[0152] The total yield of the two fractions was 20 g (52.1% of theory).

[0153] B/5: Reaction of 1,5-bis(2-pyridyl)pentane-1,3,5-trione withGaseous Ammonia:

[0154] In a 4 l flask provided with a stirrer, water separator andreflux condenser, a solution of 174 g (0.649 mol) of1,5-bis-(2-pyridyl)pentane-1,3,5-trione in 2000 ml of absolute ethanolwas heated to 40° C. 77 g of ammonia gas were passed into the darksolution over a period of 3 hours while increasing the temperature to afinal temperature of 55° C. The reaction mixture was heated to 57° C.and, while continuing to introduce a gentle stream of ammonia gas, about1050 ml of ethanol/water were separated off over a period of 3 hourswhile increasing the temperature to a final temperature of 78° C. Towardthe end of the removal of ethanol/water, another 103 g of ammonia gaswere fed in. The dark brown reaction solution was allowed to cool toroom temperature while stirring and allowed to stand over the weekend.he remaining alcohol was then removed at 60° C./25 hPa on a rotaryevaporator, the dark brown, crystalline residue was admixed with 800 mlof water, stirred at room temperature and allowed to stand overnight.

[0155] The crystalline mass was filtered off with suction, washed threetimes with 100 ml of water and twice with 30 ml each time of coldethanol.

[0156] Drying in a vacuum drying oven at 50° C. gave 156.2 g of crudeproduct of the compound

[0157] which, however, had a water content determined by the KarlFischer method of 15.5% and a solids content determined by drying at150° C. of 83.8%. Drying again at 50° C. in a vacuum drying oven finallygave 133 g of product having a solids content determined by drying at150° C. of 90.6%. The yield was therefore about 80% of theory. Themelting range was 153-158° C.

[0158] Reaction Step C:

[0159] C/1: Reaction of 2,6-bis(2-pyridyl)-4(1H)pyridinone withPhosphorus Oxide Chloride:

[0160] 750 ml of phosphorus oxide chloride were placed in a 2 l flaskprovided with a stirrer and reflux condenser and, at room temperature,140 g (0.561 mol) of the 2,6-bis(2-pyridyl)-4(1H)pyridinone obtained inreaction B/5 were added a little at a time. The reaction mixture wasrefluxed at about 107° C. for 7 hours, subsequently allowed to cool toroom temperature and allowed to stand overnight. The excess phosphorusoxide chloride was distilled off at 65° C./35 hPa, the dark mass whichremained was broken up in a mortar, suspended in 300 ml of n-hexane andthen filtered off with suction and washed with a little n-hexane. Dryingin a vacuum drying oven at 40° C. gave 248 g of solid which wasdissolved in 2000 ml of water. The solution was heated to 35° C. andneutralized by addition of sodium carbonate a little at a time (vigorousfoaming!). After stirring for one hour, the dark brown, crystallineprecipitate was filtered off with suction, washed three times with 100ml each time of water and dried at 50° C. in a vacuum drying oven. Thisgave 143 g of crude product of the compound

[0161] which had a melting point of 145-148° C.

[0162] Recrystallization of the crude product from 2500 ml of ethylacetate with addition of activated carbon gave light-brown crystalswhich were filtered off with suction and dried at 50° C. in a vacuumdrying oven. The yield was 57 g and the melting point was 150-152° C.

[0163] The filtrate from the recrystallization was concentrated to avolume of about 200 ml on a rotary evaporator, cooled in ice, theprecipitate was filtered off, washed with a little ethyl acetate anddried at 50° C. in a vacuum drying oven. The yield from the secondarycrystallization was 42.2 g and the melting point was 149-151° C.

[0164] The total yield of the two fractions was 99.2 g (66.1% oftheory).

[0165] C/2: Reaction of 2,6-bis(2-pyridyl)-4(1H)pyridinone with aPhosphorus oxide chloride/toluene mixture:

[0166] 14 g (46 mmol) of the 2,6-bis-(2-pyridyl)-4(1H)pyridinone CH₃COOHobtained in reaction B/2 and a mixture of 50 ml of phosphorus oxidechloride with 50 ml of toluene were placed in a 500 ml flask providedwith a stirrer and reflux condenser, heated to 103° C. and refluxed atthis temperature for 5.5 hours. The mixture was subsequently allowed tocool to room temperature and allowed to stand overnight.

[0167] The phosphorus oxide chloride/toluene mixture was removed underreduced pressure on a rotary evaporator, the crystalline residue wasdissolved in 300 ml of water and the solution was neutralized with solidsodium carbonate. This resulted in precipitation of a virtually whitesolid which was filtered off with suction and washed twice with 30 mleach time of water. Drying in a vacuum drying oven at 50° C. gave 10 g(82% of theory) of virtually colorless crude product of the compound

[0168] which had a melting point of 148-150° C.

We claim:
 1. A process for preparing terpyridines of the formula I

in which R are hydrogens or identical C₁-C12-alkyl or C₁-C₁₂-alkoxyradicals and n is 0, 1, 2, 3 or 4 and is the same for both sets of 20radicals R, by successive reaction steps comprising A) condensation of aC₁-C₄-alkyl pyridine-2-carboxylate derivative of the formula a

 with acetone in an aprotic solvent in the presence of a base, B)reaction of the 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivative of theformula b

obtained in reaction step A with ammonia or ammonium salts (NH₄)_(q)Ywith removal of the water of reaction formed, where the variable Y in(NH₄)_(q)Y is the anion of the parent q-basic acid H_(q)Y of theammonium salt, and C) chlorination of the2,6-bis(2-pyridyl)-4(1H)pyridinone derivative of the formula c obtainedin reaction step B,

 where Z is NH in the case of a reaction with ammonia in reaction step Band is NH₂ ^(⊕)[Y_(1/q)]^(⊖) in the case of a reaction with ammoniumsalt (NH₄)_(q)Y in reaction step B, wherein the reaction step A ispreceded by a reaction step A′ in which the C₁-C₄-alkylpyridine-2-carboxylate derivative of the formula a is obtained by A′)acid hydrolysis of a 2-cyanopyridine derivative of the formula a′

 by means of an anhydrous inorganic acid or its anhydride in thepresence of water and a C₁-C₄-alkanol, with an equimolar amount of waterbeing added to the 2-cyanopyridine derivative of the formula a′ prior toaddition of the anhydrous inorganic acid or its anhydride, the base usedin reaction step A is an alkali metal C₁-C₄-alkoxide or alkaline earthmetal C₁-C₄-alkoxide, the removal of the water of reaction in reactionstep B is carried out using a C₁-C₄-alkanol as entrainer and thechlorination of the 2,6-bis(2-pyridyl)-4(1H)pyridinone derivative of theformula c in reaction step C is carried out using phosphorus oxidechloride (POCl₃) or using a mixture comprising phosphorus oxide chlorideand at least one organic solvent selected from the group consisting oftoluene, o-xylene, m-xylene and p-xylene.
 2. A process as claimed inclaim 1, wherein the base used in reaction step A is an alkali metalC₁-C₄-alkoxide.
 3. A process as claimed in claim 1, wherein the baseused in reaction step A is sodium C₁-C₄-alkoxide.
 4. A process asclaimed in claim 1, wherein the base used in reaction step A is sodiumethoxide.
 5. A process as claimed in claim 1, wherein the removal of thewater of reaction in reaction step B is carried out using ethanol,n-propanol, i-propanol or n-butanol as entrainer.
 6. A process asclaimed in claim 1, wherein the removal of the water of reaction inreaction step B is carried out using ethanol as entrainer.
 7. A processas claimed in claim 1, wherein the chlorination of the2,6-bis(2-pyridyl)-4(1H)pyridinone derivative of the formula b iscarried out using phosphorus oxide chloride (POCl₃) or using a mixturecomprising phosphorus oxide chloride and toluene.
 8. A process forpreparing C₁-C₄-alkyl pyridine-2-carboxylate derivatives of the formulaa

in which R is hydrogen or a C₁-C₁₂-alkyl or C₁-C₁₂-alkox radical and nis 0, 1, 2, 3 or 4, by acid hydrolysis of a 2-cyanopyridine derivativeof the formula a′

by means of an anhydrous inorganic acid or its anhydride in the presenceof water and a C₁-C₄-alkanol, wherein an equimolar amount of water isadded to the 2-cyanopyridine derivative of the formula a′ prior toaddition of the anhydrous inorganic acid or its anhydride.
 9. A processfor preparing 1,5-bis(2-pyridyl)pentane-1,3,5-trione derivatives of theformula b

in which R are hydrogens or identical C₁-C₁₂-alkyl or C₁-C₁₂-alkoxyradicals and n is 0, 1, 2, 3 or 4 and is the same for both sets ofradicals R, by condensation of the C₁-C₄-alkyl pyridine-2-carboxylatederivative of the formula a

with acetone in an aprotic solvent in the presence of an alkali metalC₁-C₄-alkoxide or alkaline earth metal C₁-C₄-alkoxide as base.
 10. Aprocess as claimed in claim 9, wherein the base used is an alkali metalC₁-C₄-alkoxide.
 11. A process as claimed in claim 9, wherein the baseused is sodium C₁-C₄-alkoxide.
 12. A process as claimed in claim 9,wherein the base used is sodium methoxide.
 13. A process for preparing2,6-bis(2-pyridyl)-4(1H)pyridinone derivatives of the formula c

in which R are hydrogens or identical C₁-C₁₂-alkyl or C₁-C₁₂-alkoxyradicals, n is 0, 1, 2, 3 or 4 and is the same for both sets of radicalsR, Z is NH or NH₂ ^(⊕)[Y_(1/q)]^(⊖) and Y is the anion of a q-basic acidH_(q)Y, by reacting the 1,5-bis(2-pyridyl)pentane-1,3,5-trionederivative of the formula b

with ammonia or ammonium salts (NH₄)_(q)Y with removal of the water ofreaction formed, wherein the removal of the water of reaction is carriedout using a C₁-C₄-alkanol as entrainer.
 14. A process as claimed inclaim 13, wherein the removal of the water of reaction is carried outusing ethanol, n-propanol, i-propanol or n-butanol as entrainer.
 15. Aprocess as claimed in claim 13, wherein the removal of the water ofreaction is carried out using ethanol as entrainer.
 16. A process forpreparing terpyridines of the formula I

in which R are hydrogens or identical C₁-C₁₂-alkyl or C₁-C₁₂-alkoxyradicals, n is 0, 1, 2, 3 or 4 and is the same for both sets of radicalsR, Z′ is nitrogen or NH^(⊕) ([Y_(1/q)]^(⊖) and Y is the acid anion of aq-basic acid H_(q)Y, by chlorination of the2,6-bis(2-pyridyl)-4(1H)pyridinone derivative of the formula b (b),

where Z is NH or NH₂ ^(⊕) [Y_(1/q)]^(⊖), wherein the chlorination iscarried out using phosphorus oxide chloride (POCl₃) or using a mixturecomprising phosphorus oxide chloride and at least one organic solventselected from the group consisting of toluene, o-xylene, m-xylene andp-xylene.
 17. A process as claimed in claim 16, wherein the chlorinationis carried out using phosphorus oxide chloride (POCl₃) or using amixture comprising phosphorus oxide chloride and toluene.